Despite dramatic advances in the treatment of heart disease over the past three decades, coronary artery disease (CAD) remains the leading cause of death in the Western world (“Mortality from coronary heart disease and acute myocardial infarction” Morbidity & Mortality Weekly Report 50:90-93, 2001; incorporated herein by reference). More specifically, while preventative measures and “mechanical” revascularization strategies (angioplasty and bypass surgery) have resulted in five year survival rates in excess of 80% for individuals who are candidates for such therapies, treatment options remain limited when coronary disease has progressed to diffuse, occlusive disease, and/or infarction (American Heart Association, Heart and Stroke Statistical Update, 2003; incorporated herein by reference). The two-year survival rate for individuals with such advanced coronary artery disease is as low as 20% (Anyanwu et al. “Prognosis after heart transplantation: transplants alone cannot be the solution for end stage heart failure” BMJ 326:509-510, 2003; incorporated herein by reference).
Each year, almost 1.1 million Americans suffer an acute myocardial infarction (American Heart Association, Heart and Stroke Statistical Update, 2003; incorporated herein by reference). Early intervention can limit infarct size and improve early survival (Mitchell et al. “Left ventricular remodeling in the year after first anterior myocardial infarction: a quantitative analysis of contractile segment lengths and ventricular shape” J. Am. Coll. Cardiol 19:1136-44, 1992; Migrino et al. “End-systolic volume index at 90 and 180 minutes into reperfusion therapy for acute myocardial infarction is a strong predictor of early and late mortality” Circulation 96:116-121, 1997; Boyle et al. “Limitation of infarct expansion and ventricular remodeling by late reperfusion. Study of time course and mechanism in a rat model” Circulation 88:2872-83, 1993; each of which is incorporated herein by reference). However, 20% of those patients surviving an acute myocardial infarction will develop significant left ventricular dilatation with a left ventricular end-systolic volume index (LVESVI) of less than 60 mL/m2. The GUSTO I trial (Migrino et al. “End-systolic volume index at 90 and 180 minutes into reperfusion therapy for acute myocardial infarction is a strong predictor of early and late mortality” Circulation 96:116-121, 1997; incorporated herein by reference) documented that left ventricular dilatation following myocardial infarction is an independent and significant predictor of mortality. Therefore, whereas early survival after myocardial infarction may be predicated by the timeliness and adequacy of appropriate reperfusion therapy, long-term prognosis is strongly dependent on subsequent changes in left ventricular geometry and function These are the determinants of congestive heart failure (Mitchell et al. “Left ventricular remodeling in the year after first anterior myocardial infarction: a quantitative analysis of contractile segment lengths and ventricular shape” J. Am. Coll. Cardiol. 19:1136-44, 1992; Gheorghiade et al. “Chronic heart failure in the United States, a manifestation of coronary artery disease” Circulation. 97:282-89, 1998; White et al. “Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction” Circulation 76(1):44-51, 1987; each of which is incorporated herein by reference).
Congestive heart failure (CHF), which can result from an acute myocardial infarction, currently affects over 5 million people in the United States (National Heart Lung and Blood Institute National Institutes of Health Data Fact Sheet: congestive heart failure in the United States: A new epidemic. NHLBI web site. www/nhlbi.nih.gov/health/public/heart/other/chf.htm; O'Connell et al. “Economic impact of heart failure in the United States: time for a different approach” J. Heart Lung Transplant. 13:S107-S112, 1994; each of which is incorporated herein by reference). Medical therapies, despite some progress, still confer only a <50% one-year survival in patients with the most severe clinical manifestations of end-stage CHF (Rose et al. “Long-term use of a left ventricular assist device for end-stage heart failure” NEJM 345(20):1435-43, 2001; incorporated herein by reference). Despite its clinical effectiveness, heart transplantation is a therapy with little epidemiological significance in the fight against heart failure (Taylor et al. “The registry of the international society of heart and lung transplantation: 20th official adult heart transplant report-2003” J. Heart Lung Transplant. 22(6):616-624, 2003; incorporated herein by reference). As a result, cell-based therapies for repair and regeneration of infarcted myocardium have been proposed to treat patients suffering from chronic heart failure (Chiu et al. “Cellular cardiomyoplasty: myocardial regeneration with satellite cell implantation” Ann. Thor. Surg. 60:12-8, 1995; Pagani et al. “Autologous skeletal myoblasts transplanted to ischemia-damaged myocardium in humans” J. Am. Coll. Cardiol. 41:879-888, 2003; Ghostine et al. “Long-term efficacy of myoblast transplantation on regional structure and function after myocardial infarction” Circulation 106[suppl I]:I131-6, 2002; Dorfmaan et al. “Myocardial tissue engineering with autologous myoblast implantation” J. Thor. Cardiovasc. Surg. 116:744-51, 1988; Taylor et al. “Regenerating functional myocardium: improved performance after skeletal myoblast transplantation” Nat. Med 4(8):929-33, 1998; Retuerto et al. “Angiogenic pre-treatment improves the efficacy of cellular cardiomyoplasty performed with fetal cardiomyocyte implantation” J. Thorac. Cardiovasc. Surg. 127:1-11, 2004; Jain et al. “Cell therapy attenuates deleterious ventricular remodeling and improves cardiac performance after myocardial infarction” Circulation 103:1920-27, 2001; Reinecke et al. “Evidence for fusion between cardiac and skeletal muscle cells” Circ. Res. 94(6):e56-60, 2004; McConnell et al. “Correlation of autologous skeletal myoblast survival with changes in left ventricular remodeling in dilated ischemic heart failure” J. Thorac. Cardiovasc. Surg. 2004 (in press); Kessler et al. “Myoblast cell grafting into heart muscle: cellular biology and potential applications” Annu. Rev. Physiol. 61:219-42, 1999; Yoo et al. “Heart cell transplantation improves heart function in dilated cardiomyopathic hamsters” Circulation. 102(19 Suppl 3):III204-9, 2000; Koh et al. “Stable fetal cardiomyocyte grafts in the hearts of dystrophic mice and dogs” J. Clin. Invest. 96(4):2034-42, 1995; Klug et al. “Genetically selected cardiomyocytes from differentiating embronic stem cells form stable intracardiac grafts” J. Clin. Invest. 98(1):216-24, 1996; Jackson et al. “Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells” J. Clin. Invest. 107(11): 1395-402, 2001; Kocher et al. “Neovascularization of ischemic myocardium by human bone marrow derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function” Nature Medicine 7:430-436, 2001; Kamihata et al. “Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines” Circulation 104:1046-1052, 2001; Orlic et al. “Transplanted adult bone marrow cells repair myocardial infarcts in mice” Ann. N.Y. Acad. Sci. 938:221-9, discussion 229-30, 2001; Orlic et al. “Mobilized bone marrow cells repair the infarcted heart, improving function and survival” Proc. Natl. Acad. Sci. U.S.A. (98): 10344-9, 2001; Balsam et al. “Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium” Nature 428(6983):668-73, 2004; Reinecke et al. “Taking the toll after cardiomyocyte grafting: a reminder of the importance of quantitative biology” J. Mol. Cell. Card. 34:251-253, 2002; Perin et al. “Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure” Circulation 107:2294-2302, 2003; Tse et al. “Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation” Lancet 361:47-49, 2003; Kamihata et al. “Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines” Circulation 104:1046-1052, 2001; each of which is incorporated herein by reference). Immature cells are grafted into the heart in key areas of myocardial dysfunction with the goal of angiogenesis, vasculogenesis, and/or myogenesis to promote functional and geometric restoration. Unfortunately, current results in human clinical trials demonstrate that cellular graft survival number is very poor with typically <1% of autologous myoblasts surviving implantation (Pagani et al. “Autologous skeletal myoblasts transplanted to ischemia-damaged myocardium in humans.” J. Am. Coll. Cardiol. 41:879-888, 2003; incorporated herein by reference). The reason for such poor cell survival and engraftment is unknown.
Cell transfer is generally thought to provide for the regeneration of cardiac function in the setting of myocardial infarction by: (1) “repopulating” scarred myocardium with contractile myocytes; (2) providing a “scaffolding” to diminish further remodeling of the thinned, injured ventricle; and/or (3) serving as a vehicle for the angiogenic stimulation of ischemic myocardium (Scorsin et al. “Comparison of the effects of fetal cardiomyocyte and skeletal myoblast transplantation on postinfarction left ventricular function” J. Thorac. Cardiovasc. Surg. 119:1169-75, 2000; Jain et al. “Cell therapy attenuates deleterious ventricular remodeling and improves cardiac performance after myocardial infarction” Circulation 103:1920-1927, 2001; Suzuki et al. “Development of a novel method for cell transplantation through the coronary artery” Circulation 102[suppl III]:III-359-111-364, 2000; Orlic et al. “Bone marrow cells regenerate infarcted myocardium” Nature 410:701-704, 2001; Wang et al. “Marrow stromal cells for cellular cardiomyoplasty: feasibility and potential” J. Thorac. Cardiovasc. Surg. 120:999-1006, 2000; Tomita et al. “Autologous transplantation of bone marrow cells improves damaged heart heart function” Circulation 100[suppl II]:II-247-II-256, 1999; Reinecke et al. “Survival, Integration, and differentiation of cardiomyocyte grafts: a study in normal and injured rat hearts” Circulation 100:193-202, 1999; Sakai et al. “Cardiothoracic transplantation. Fetal cell transplantation: a comparison of three cell types” J. Thorac. Cardiovasc. Surg. 118:715-25, 1999; Chedrawy et al. “Incorporation and integration of implanted myogenic and stem cells into native myuocardial fibers: anatomic basis for functional improvements” J. Thorac. Cardiovasc. Surg. 124:584-90, 2002; Klug et al. “Genetically selected cardiomyocytes from differentiating embryonic stem cells form stable intracardiac grafts” J. Clin. Invest. 98:216-224, 1996; Atkins et al. “Intracardiac transplantation of skeletal myoblasts yields two populations of striated cells in situ” Ann. Thorac. Surg. 67:124-9, 1999; Leor et al. “Transplantation of fetal myocardial tissue into the infarcted myocardium of rat. A potential method for repair of infarcted myocardium?” Circulation 94 [suppl II]:II-332-II-336, 1996; Zhang et al. “Cardiomyocyte grafting for cardiac repair: graft cell death and anti-death strategies” J. Mol. Cell. Cardiol. 33:907-921, 2001; Li et al. “Natural history of fetal rat cardiomyocytes transplanted into adult rat myocardial scar tissue” Circulation 96[suppl II]:II-179-II-187, 1997; Taylor et al. “Regenerating functional myocardium: improved performance after skeletal myoblast transplantation” Nature Medicine 4:929-933, 1998; Menasché, “Cell therapy of heart failure” C R Biologies 325:731-738, 2002, Oh et al. “Cardiac progenitors from adult myocardium: homing, differentiation and fusion after infarction” Proc. Natl. Acad. Sci. USA 100:12313-18, 2003; Terada et al. “Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion” Nature 416:542-5, 2002; Ying et al. “Changing potency by spontaneous fusion” Nature 416:545-8, Apr. 4, 2002; each of which is incorporated herein by reference). It is unknown which if any of these mechanisms is relevant to the putative efficacy of cellular cardiomyoplasty (CCM). In this regard, the typically extremely inefficient (<10%) observed engraftment of cells into areas of myocardial scar has been cited as a potential explanation for the relatively limited improvements in ventricular function noted after cell implantation in animal studies (Pagani et al. “Autologous skeletal myoblasts transplanted to ischemia-damaged myocardium in humans: Histological analysis of cell survival and differentiation” J. Am. Coll. Cardiol. 41:879-88, 2003; Matsushita et al. “Formation of cell junctions between grafted and host cardiomyocytes at the border zone of rat myocardial infarction” Circulation 100[suppl II]:II-262-II-268, 1999; Kehat et al. “Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes” J. Clin. Invest. 108:407-414, 2001; Boheler et al. “Differentiation of pluripotent embryonic stem cells into cardiomyocytes” Circ. Res. 91:189-201, 2002; Toma et al. “Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart” Circulation 105:93-98, 2002; Tambara et al. “Transplanted skeletal myoblasts can fully replace the infracted myocardium when they survive in the host in large numbers” Circulation 108[suppl II]:II-259-II-263, 2003; Minami et al. “Skeletal muscle meets cardiac muscle” J. Am. Coll. Cardiol. 41:1084-6, 2003; Ghostine et al. “Long-term efficacy of myoblast transplantation on regional structure and function after myocardial infarction” Circulation 100[suppl I]:I-131-I-136, 2002; each of which is incorporated herein by reference), and has raised doubts as to the importance of the persistent physical presence of cell implants in myocardial scar, as opposed to their potential role as a transient mediator of angiogenesis (Scorsin et al. “Comparison of the effects of fetal cardiomyocyte and skeletal myoblast transplantation on postinfarction left ventricular function” J. Thorac. Cardiovasc. Surg. 119:1169-75, 2000; Reinecke et al. “Survival, Integration, and differentiation of cardiomyocyte grafts: a study in normal and injured rat hearts” Circulation 100:193-202, 1999; Zhang et al. “Cardiomyocyte grafting for cardiac repair: graft cell death and anti-death strategies” J. Mol. Cell. Cardiol. 33:907-921, 2001; Menasche, “Cell therapy of heart failure” C. R. Biologies 325:731-738, 2002; each of which is incorporated herein by reference). Also, while the efficacy of CCM has been idealized to involve the differentiation of stem cells into functional cardiomyocytes, evidence of such differentiation may have been confounded by the potential occurrence of cell fusion between implanted stem cells and host myocytes (Oh et. al. “Cardiac progenitors from adult myocardium: homing, differentiation and fusion after infarction” Proc. Natl. Acad. Sci. USA 100:12313-18, 2003; Terada et al. “Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion” Nature 416:542-5, 2002; Ying et al. “Changing potency by spontaneous fusion” Nature 416:545-48, Apr. 4, 2002; each of which is incorporated herein by reference). Skeletal myoblast transplantation though has been demonstrated to provide functional advantages over fibroblast implants in cardiomyoplasty studies (Scorsin et al. “Comparison of the effects of fetal cardiomyocyte and skeletal myoblast transplantation on postinfarction left ventricular function” J. Thorac. Cardiovasc. Surg. 119:1169-75, 2000; Jain et al. “Cell therapy attenuates deleterious ventricular remodeling and improves cardiac performance after myocardial infarction” Circulation 103:1920-1927, 2001; Sakai et al. “Cardiothoracic transplantation. Fetal cell transplantation: a comparison of three cell types” J. Thorac. Cardiovasc. Surg. 118:715-25, 1999; Taylor et al. “Regenerating functional myocardium: improved performance after skeletal myoblast transplantation” Nature Medicine 4:929-933, 1998; each of which is incorporated herein by reference).
Given the use of cellular cardiomyoplasty to treat heart disease and the progress being made in this field, there remains a need for treatments of damage to heart tissue using cellular cardiomyoplasty. Also, given the recent advent of this treatment, the issue remains of how this treatment method can best be used in the treatment of patients suffering with various types and severity of heart disease.